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Drosophila tumor suppressor genes have revealed molecular pathways that control tissue growth, but mechanisms that regulate mitogenic signaling are far from understood. Here we report that the Drosophila TSG tumorous imaginal discs (tid), whose phenotypes were previously attributed to mutations in a DnaJ-like chaperone, are in fact driven by the loss of the N-linked glycosylation pathway component ALG3. tid/alg3 imaginal discs display tissue growth and architecture defects that share characteristics of both neoplastic and hyperplastic mutants. Tumorous growth is driven by inhibited Hippo signaling, induced by excess Jun N-terminal kinase (JNK) activity. We show that ectopic JNK activation is caused by aberrant glycosylation of a single protein, the fly tumor necrosis factor (TNF) receptor homolog, which results in increased binding to the continually circulating TNF. Our results suggest that N-linked glycosylation sets the threshold of TNF receptor signaling by modifying ligand-receptor interactions and that cells may alter this modification to respond appropriately to physiological cues.

Tumor necrosis factor (TNF)‐α is a highly conserved proinflammatory cytokine with important functions in immunity, tissue repair, and cellular homeostasis. Due to the simplicity of the Drosophila TNF‐TNF receptor (TNFR) system and a broad genetic toolbox, the fly has played a pivotal role in deciphering the mechanisms underlying TNF‐mediated physiological and pathological functions. In this review, we summarize the recent advances in our understanding of how local and systemic sources of Egr/TNF contribute to its antitumor and tumor‐promoting properties, and its emerging functions in adaptive growth responses, sleep regulation, and adult tissue homeostasis. The recent annotation of TNF as an adipokine and its indisputable contribution to obesity‐ and cancer‐associated metabolic diseases have provoked a new area of research focusing on its dual function in regulating immunity and energy homeostasis. Here, we discuss the role of TNFR signaling in coupling immune and metabolic processes and how this might be relevant in the adaption of host to environmental stresses, or, in the case of obesity, promote metabolic derangements and disease. [ABSTRACT FROM AUTHOR]

Target of rapamycin (TOR) is a central regulator of cellular and organismal growth in response to nutrient conditions. In a genetic screen for novel TOR interactors in Drosophila melanogaster, we have identified the clathrin-uncoating ATPase Hsc70-4, which is a key regulator of endocytosis. We present genetic evidence that TOR signaling stimulates bulk endocytic uptake and inhibits the targeted endocytic degradation of the amino acid importer Slimfast. Thus, TOR simultaneously down-regulates aspects of endocytosis that inhibit growth and up-regulates potential growth-promoting functions of endocytosis. In addition, we find that disruption of endocytosis leads to changes in TOR and phosphatidylinositol-3 kinase activity, affecting cell growth, autophagy, and rapamycin sensitivity. Our data indicate that endocytosis acts both as an effector function downstream of TOR and as a physiologically relevant regulator of TOR signaling.

Drosophila MCRS2 (dMCRS2; MCRS2/MSP58 and its splice variant MCRS1/p78 in humans) belongs to a family of forkhead-associated (FHA) domain proteins. Whereas human MCRS2 proteins have been associated with a variety of cellular processes, including RNA polymerase I transcription and cell cycle progression, dMCRS2 has been largely uncharacterized. Recent data show that MCRS2 is purified as part of a complex containing the histone acetyltransferase MOF (males absent on first) in both humans and flies. MOF mediates H4K16 acetylation and regulates the expression of a large number of genes, suggesting that MCRS2 could also have a function in transcription regulation. Here, we show that dMCRS2 copurifies with RNA polymerase II (RNAP II) complexes and localizes to the 5' ends of genes. Moreover, dMCRS2 is required for optimal recruitment of RNAP II to the promoter regions of cyclin genes. In agreement with this, dMCRS2 is required for normal levels of cyclin gene expression. We propose a model whereby dMCRS2 promotes gene transcription by facilitating the recruitment of RNAP II preinitiation complexes (PICs) to the promoter regions of target genes. [ABSTRACT FROM AUTHOR]

It is well established that tumor necrosis factor (TNF) plays an instrumental role in orchestrating the metabolic disorders associated with late stages of cancers. However, it is not clear whether TNF/TNF receptor (TNFR) signaling controls energy homeostasis in healthy individuals. Here, we show that the highly conserved Drosophila TNFR, Wengen (Wgn), is required in the enterocytes (ECs) of the adult gut to restrict lipid catabolism, suppress immune activity, and maintain tissue homeostasis. Wgn limits autophagy-dependent lipolysis by restricting cytoplasmic levels of the TNFR effector, TNFR-associated factor 3 (dTRAF3), while it suppresses immune processes through inhibition of the dTAK1/TAK1-Relish/NF-κB pathway in a dTRAF2-dependent manner. Knocking down dTRAF3 or overexpressing dTRAF2 is sufficient to suppress infection-induced lipid depletion and immune activation, respectively, showing that Wgn/TNFR functions as an intersection between metabolism and immunity allowing pathogen-induced metabolic reprogramming to fuel the energetically costly task of combatting an infection.

Multicellular organisms have evolved organs and tissues with highly specialized tasks. For instance, nutrients are assimilated by the gut, sensed, processed, stored, and released by adipose tissues and liver to provide energy consumed by peripheral organ activities. The function of each organ is modified by local clues and systemic signals derived from other organs to ensure a coordinated response accommodating the physiological needs of the organism. The intestine, which represents one of the largest interfaces between the internal and external environment, plays a key role in sensing and relaying environmental inputs such as nutrients and microbial derivatives to other organs to produce systemic responses. In turn, gut physiology and immunity are regulated by multiple signals emanating from other organs including the brain and the adipose tissues. In this review, we highlight physiological processes where the gut serves as a key organ in coupling systemic signals or environmental cues with organism growth, metabolism, immune activity, aging, or behavior. Robust strategies involving intraorgan and interorgan signaling pathways have evolved to preserve gut size in homeostatic conditions and restrict growth during damage-induced regenerative phases. Here we review some of the mechanisms that maintain gut size homeostasis and point out known examples of homeostasis-breaking events that promote gut plasticity to accommodate changes in the external or internal environment. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Adult Stem Cells, Tissue Renewal, and Regeneration > Environmental Control of Stem Cells Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration., (© 2020 Wiley Periodicals, Inc.)

Body size is an intrinsic property of living organisms that is intimately linked to the developmental program to produce fit individuals with proper proportions. Final size is the result of both genetic determinants and sophisticated mechanisms adapting size to available resources. Even though organs grow according to autonomous programs, some coordination mechanisms ensure that the different body parts adjust their growth with the rest of the body. In Drosophila, Dilp8, a hormone of the Insulin/Relaxin family is a key player in this inter-organs coordination and is required together with its receptor Lgr3 to limit developmental variability. Recently, the transcriptional co-activator Yki (homologue of YAP/TAZ factors in mammals) was shown to regulate dilp8 expression and contribute to the coordination of organ growth in Drosophila., (© 2017 médecine/sciences – Inserm.)